scholarly journals The evolving genetic risk for sporadic ALS

Neurology ◽  
2017 ◽  
Vol 89 (3) ◽  
pp. 226-233 ◽  
Author(s):  
Summer B. Gibson ◽  
Jonathan M. Downie ◽  
Spyridoula Tsetsou ◽  
Julie E. Feusier ◽  
Karla P. Figueroa ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Repeat Expansion ◽  
European Ancestry ◽  
Protein Coding ◽  
University Of Utah ◽  
Sporadic Als ◽  
Variant Frequency ◽  
Deleterious Variant ◽  
Genetic Burden ◽  
Normal Controls

Objective:To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)–associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity.Methods:Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls.Results:Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls.Conclusions:Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.

scholarly journals Rare variants in MYH15 modify amyotrophic lateral sclerosis risk

2019 ◽  
Vol 28 (14) ◽  
pp. 2309-2318 ◽  
Author(s):  
Hyerim Kim ◽  
Junghwa Lim ◽  
Han Bao ◽  
Bin Jiao ◽  
Se Min Canon ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Risk ◽  
Genetic Factors ◽  
Rare Variants ◽  
Genetic Interaction ◽  
Repeat Expansion ◽  
Genetic Screen ◽  
Genetic Components ◽  
Sporadic Als ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and sporadic ALS (sALS) using limited samples. We first identified 135 candidate genetic modifiers of C9ALS using whole-genome sequencing (WGS) of extreme C9ALS cases diagnosed ~30 years apart. We then performed an unbiased genetic screen using a Drosophila model of the G4C2 repeat expansion with the genes identified from WGS analysis. This genetic screen identified the novel genetic interaction between G4C2 repeat-associated toxicity and 18 genetic factors, suggesting their potential association with C9ALS risk. We went on to test if 14 out of the 18 genes, those which were not known to be risk factors for ALS previously, are also associated with ALS risk in sALS cases. Gene-based-statistical analyses of targeted resequencing and WGS were performed. These analyses together reveal that rare variants in MYH15 represent a likely genetic risk factor for ALS. Furthermore, we show that MYH15 could modulate the toxicity of dipeptides produced from expanded G4C2 repeat. Our study presented here demonstrates the power of combining WGS with fly genetics to facilitate the discovery of fundamental genetic components of complex traits with a limited number of samples.

scholarly journals Common and rare genetic variants that could contribute to severe otitis media in an Australian Aboriginal population

2021 ◽  
Author(s):  
Sarra E Jamieson ◽  
Michaela Fakiola ◽  
Dave Tang ◽  
Elizabeth Scaman ◽  
Genevieve Syn ◽  
...  
Keyword(s):  
Hair Cell ◽  
Otitis Media ◽  
Genetic Risk ◽  
Transforming Growth Factor ◽  
Rare Variants ◽  
Protein Coding ◽  
Gene Sets ◽  
Growth Factor Signalling ◽  
Rare Genetic Variants ◽  
And Function

Abstract Background Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians. Methods Illumina ® Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all≥0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥ 15) were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over ≥ 3 consecutive years). Rare (ExAC_all≤0.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways/processes relevant to OM. Results FUMA analysis identified two plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G=3.62x10 -6) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G=3.67x10 -6) encoding neuronal regeneration related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled ≥ 15) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for “abnormal ear” (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signalling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly. Conclusions This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children.

Epicardial adipose tissue: the genetics behind an emerging cardiovascular marker

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J.A Sousa ◽  
M.G Serrao ◽  
M Temtem ◽  
A Pereira ◽  
M Santos ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cardiovascular Risk ◽  
Genetic Risk ◽  
Epicardial Adipose Tissue ◽  
Genetic Risk Score ◽  
Renin Angiotensin System ◽  
Epicardial Fat ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Genetic Burden

Abstract Background Increasing evidence points epicardial adipose tissue (EAT) as an emerging cardiovascular risk marker. Whether genetic polymorphisms are associated with a higher EAT burden is still unknow. Genetic risk score (GRS) is an emerging method that attempts to establish correlation between single nucleotide polymorphisms (SNPs) and clinical phenotypes. Aim Evaluate the role of genetic burden and its association to EAT. Methods 996 patients (mean age 59±8, 78% male) were prospectively enrolled in a single center. EAT was measured on cardiac CT using a modified simplified method. Patients were divided into 2 groups (above vs. below the median EAT volume). We studied different polymorphisms across the following gene-regulated pathways: oxidation, renin-angiotensin system, cellular, diabetes/obesity and dyslipidemia pathways. Genotyping was performed by TaqMan allelic discrimination assay. A multiplicative genetic risk score (mGRS) was constructed and represents the genetic burden of the different polymorphisms studied. To evaluate the relation between genetics and EAT volume, we compared both groups by: global mGRS, gene cluster/axis mGRS and individual SNPs. Results Patients with above-median EAT volume were older, had higher body mass index (BMI) and higher prevalence of hypertension, diabetes and dyslipidemia (p<0.05). Patients with higher EAT volumes presented a higher global mean GRS (p<0.001), with the latter remaining an independent predictor for higher EAT volumes (OR 1.3, 95% CI 1.2–1.5), alongside age and BMI. In the analysis by gene clusters, patients with more epicardial fat consistently presented a higher polymorphism burden (translated by a higher mGRS level) across numerous pathways: oxidation, renin-angiotensin system, cellular, diabetes/obesity and dyslipidemia. After adjusting for confounders and other univariate predictors of higher fat volume, the following have emerged as independently related to higher EAT volumes: mGRS comprising the genes of different clusters, age and BMI. Amongst the 33 genes analyzed, only MTHFR677 polymorphisms (a gene with a critical role in regulating plasma homocysteine levels) emerged as significantly related to higher EAT volumes in our population (OR 1.4, 95% CI: 1.100–1.684, p=0.005). Conclusion Patients with a higher polymorphism burden in genes involved in the oxidation, renin-angiotensin, cellular, diabetes/obesity and dyslipidemia pathways present higher levels of epicardial fat. This potential association seems to be independent from the expected association between epicardial fat and cardiovascular risk factors. To our knowledge, this is the first time such genetic profiling has been done, casting further insight into this complex matter. Funding Acknowledgement Type of funding source: None

scholarly journals Prevalence of C9orf72 hexanucleotide repeat expansion in Greek patients with sporadic ALS

2020 ◽  
Vol 21 (5-6) ◽  
pp. 470-472
Author(s):  
Maria Sokratous ◽  
Schottlaender Lucia ◽  
Thomas Bourinaris ◽  
Chrysoula Marogianni ◽  
Marianthi Arnaoutoglou ◽  
...  
Keyword(s):  
Repeat Expansion ◽  
Hexanucleotide Repeat ◽  
Sporadic Als ◽  
Hexanucleotide Repeat Expansion

scholarly journals 1152 Genetic Risk Of Alzheimer’S Disease Is Linked To Short Sleep Duration

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A439-A439
Author(s):  
Y Leng ◽  
K Yaffe ◽  
S Ackley ◽  
M Glymour ◽  
W Brenowitz
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Sleep Duration ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Genetic Ancestry ◽  
European Ancestry ◽  
Short Sleep Duration ◽  
Short Sleep

Abstract Introduction Sleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle-aged and older adults and estimated the causal effects of AD on sleep duration using a mendelian randomization (MR) analysis. Methods We examined 406,687 UK Biobank participants with Caucasian genetic ancestry who self-reported sleep duration at baseline (2006-2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related single nucleotide polymorphisms in individuals of European ancestry. We evaluated whether AD-GRS predicted sleep duration using linear regression, adjusting for age, sex and principle components for genetic ancestry. We also stratified the analysis by age at baseline (≤55y or >55y) and conducted a MR analysis to estimate the effect of AD (ICD-9/10 codes for AD/dementia diagnosis) on sleep duration. Results The participants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD-GRS of 0.11 (SD=0.40) (range: -1.15~1.85). Higher AD-GRS score predicted shorter sleep duration (b= -0.013, 95%CI:-0.022,-0.005), mainly among those aged over 55y (b= -0.023, 95%CI:-0.034,-0.012) and not in those 55y or younger (b= 0.006, 95%CI:-0.012,0.013); p for interaction by age=0.02. MR analysis using AD-GRS as an instrumental variable suggested that AD was associated with 1.76 hrs (b=-1.76, -2.62~ -0.90) shorter sleep duration in those aged >55y. Conclusion Using a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration. Support Dr. Leng received support from the National Institute on Aging (NIA) 1K99AG056598, and from GBHI, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-19-591141).

Epidemiology of Amyotrophic Lateral Sclerosis

2017 ◽  
Author(s):  
Éilis J O’Reilly
Keyword(s):  
Cardiovascular Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Military Personnel ◽  
Elite Athletes ◽  
Soccer Players ◽  
European Ancestry ◽  
Genetic Mutations ◽  
Sporadic Als ◽  
Lateral Sclerosis

The epidemiology of ALS is an emerging field and, like the epidemiology of cardiovascular disease and cancer in the mid last century, requires time for convergence of findings. There appears to be a genetic influence, and one study of twins found that heritability of sporadic ALS is 60%. At present it is thought that 60$ to 70% of genetic mutations responsible for fALS in populations of European ancestry are known. SOD1 mutations were the earliest discoveries in fALS. Subsequently, mutations were identified in TARDBP, which encodes TDP-43 protein found in neuronal inclusions in fALS and frontotemporal dementia (FTD). High rates of ALS have also been reported in military personnel and in certain groups of elite athletes such as soccer players.

scholarly journals Applicability of Obesity-Related SNPs and Their Effect Size Measures Defined on Populations with European Ancestry for Genetic Risk Estimation among Roma

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 516 ◽  
Author(s):  
Erand Llanaj ◽  
Péter Pikó ◽  
Károly Nagy ◽  
Gábor Rácz ◽  
Sándor János ◽  
...  
Keyword(s):  
Effect Size ◽  
Genetic Risk ◽  
Association Studies ◽  
Strong Association ◽  
European Ancestry ◽  
Risk Scores ◽  
Nucleotide Polymorphisms ◽  
Continuous Variables ◽  
Roma Population ◽  
The Impact

Investigations on the impact of genetic factors on the development of obesity have been limited regarding the Roma population—the largest and most vulnerable ethnic minority in Europe of Asian origin. Genetic variants identified from genetic association studies are primarily from European populations. With that in mind, we investigated the applicability of data on selected obesity-related single nucleotide polymorphisms (SNPs), obtained from the Hungarian general (HG) population of European origin, on the Hungarian Roma (HR) population. Twenty preselected SNPs in susceptible alleles, known to be significantly associated with obesity-related phenotypes, were used to estimate the effect of these SNPs on body mass index (BMI) and waist circumference (WC) in HG (N = 1783) and HR (N = 1225) populations. Single SNP associations were tested using linear and logistic regression models, adjusted for known covariates. Out of 20 SNPs, four located in FTO (rs1121980, rs1558902, rs9939609, and rs9941349) showed strong association with BMI and WC as continuous variables in both samples. Computations based on Adult Treatment Panel III (ATPIII) and the International Diabetes Federation’s (IDF) European and Asian criteria showed rs9941349 in FTO to be associated only with WC among both populations, and two SNPs (rs2867125, rs6548238) in TMEM18 associated with WC only in HG population. A substantial difference (both in direction and effect size) was observed only in the case of rs1801282 in PPARγ on WC as a continuous outcome. Findings suggest that genetic risk scores based on counting SNPs with relatively high effect sizes, defined based on populations with European ancestry, can sufficiently allow estimation of genetic susceptibility for Roma. Further studies are needed to clarify the role of SNP(s) with protective effect(s).

scholarly journals Genetic risk scores identify genetic aetiology of inflammatory bowel disease phenotypes

2020 ◽  
Author(s):  
M D Voskuil ◽  
L M Spekhorst ◽  
K W J van der Sloot ◽  
B H Jansen ◽  
G Dijkstra ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Genetic Risk ◽  
Smoking Behaviour ◽  
Risk Scores ◽  
Genetic Risk Scores ◽  
Disease Phenotypes ◽  
Inflammatory Bowel ◽  
Genetic Contributions ◽  
Genetic Burden

Abstract Background and Aims Inflammatory bowel disease (IBD) phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores (GRS) to disentangle the genetic contributions to IBD phenotypes. Methods Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts (cohort A, n=1,097; cohort B, n=2,156). Genetic risk scoring was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS–phenotype (FDR corrected P<.05) associations identified in cohort A were put forward for replication in cohort B. Results Crohn’s disease (CD) GRS were associated with fibrostenotic CD (R 2=7.4%, FDR=.02) and ileocaecal resection (R 2=4.1%, FDR=1.6E-03), and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis (UC) GRS (R 2=7.1%, FDR=.02) and primary sclerosing cholangitis (PSC) GRS (R 2=3.6%; FDR=.03) were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour (R 2=1.7%; FDR=.04). Conclusions Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, while colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.

scholarly journals Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

2019 ◽  
Author(s):  
Jessica Dennis ◽  
Julia Sealock ◽  
Rebecca T. Levinson ◽  
Eric Farber-Eger ◽  
Jacob Franco ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Major Depressive Disorder ◽  
Coronary Artery ◽  
Genetic Risk ◽  
European Ancestry ◽  
Major Depressive ◽  
Polygenic Score ◽  
Polygenic Scores ◽  
Artery Disease

AbstractMajor depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04–1.18; P 8.43 × 10−4) and 1.13 (95% CI, 1.07–1.20; P 4.51 × 10−6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03–1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95–1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99–1.14; P = 0.07) and 1.07 (1.01–1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

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